A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol.
A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol.
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DOI：
10.1186/s12885-016-2308-z
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发表时间：
2016-04-20
期刊：
影响因子：
3.8
通讯作者：
Barlesi F
中科院分区：
文献类型：
--
作者：
Elharrar X;Barbolosi D;Ciccolini J;Meille C;Faivre C;Lacarelle B;André N;Barlesi F
节律性口服长春瑞滨对转移性非小细胞肺癌和恶性胸膜间皮瘤有效，但到目前为止发表的所有研究都是基于各种经验的，可能是次优的方案，结果不一致。数学建模通过模拟表明，新的节律方案可以产生更好的安全性和有效性。这项Ia/Ib期试验旨在确认新的节律口服长春瑞滨方案的安全性(Ia期)和疗效(Ib期)。标准治疗失败的转移性非小细胞肺癌或恶性胸膜间皮瘤患者，表现为ECOG功能状态0-2且器官功能良好的患者将符合条件。我们的数学PK-PD模型提出了一个可供选择的每周d1、d2和d4的方案(命名为长春瑞滨理论方案)，分别为60、30和60 mg。试验招募将分两个阶段进行，因为计划有12名患者参加Ia阶段，以确认安全性并巩固模型参数的校准。根据Ia阶段的结果，并在咨询委员会做出有利决定后，延长阶段(Ib阶段)将是一项疗效研究，包括20名患者，他们将接受最优的长春瑞滨理论方案。主要终点是第Ia阶段的容差(由CTC V4.0评估)和根据RECIST 1.1对第Ib阶段的客观反应。循环血管生成生物标记物的辅助研究将是试验的一个子项目。这项正在进行的试验是第一次前瞻性地测试节律化疗中数学优化的方案。因此，这项试验可以被认为是一项概念验证研究，证明了在癌症患者中运行计算驱动的方案以确保最佳疗效/毒性平衡的可行性。欧洲CT N°：2015年-000138-31
Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile. This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0–2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial. This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer. EudraCT N°: 2015-000138-31